US5460823A - Process of preparing a water dispersible hydrophobic or aerophilic solid - Google Patents

Process of preparing a water dispersible hydrophobic or aerophilic solid Download PDF

Info

Publication number
US5460823A
US5460823A US08/187,134 US18713494A US5460823A US 5460823 A US5460823 A US 5460823A US 18713494 A US18713494 A US 18713494A US 5460823 A US5460823 A US 5460823A
Authority
US
United States
Prior art keywords
solid
suspension
process according
percent
temperature
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Expired - Lifetime
Application number
US08/187,134
Inventor
Nina M. Jensen
Per Vilstrup
Marianne Winning
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
BASF Health and Nutrition AS
Original Assignee
Danochemo AS
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Family has litigation
First worldwide family litigation filed litigation Critical https://patents.darts-ip.com/?family=8142640&utm_source=***_patent&utm_medium=platform_link&utm_campaign=public_patent_search&patent=US5460823(A) "Global patent litigation dataset” by Darts-ip is licensed under a Creative Commons Attribution 4.0 International License.
Application filed by Danochemo AS filed Critical Danochemo AS
Priority to US08/187,134 priority Critical patent/US5460823A/en
Application granted granted Critical
Publication of US5460823A publication Critical patent/US5460823A/en
Anticipated expiration legal-status Critical
Expired - Lifetime legal-status Critical Current

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1629—Organic macromolecular compounds
    • A61K9/1658—Proteins, e.g. albumin, gelatin
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
    • A23L5/00—Preparation or treatment of foods or foodstuffs, in general; Food or foodstuffs obtained thereby; Materials therefor
    • A23L5/40—Colouring or decolouring of foods
    • A23L5/42—Addition of dyes or pigments, e.g. in combination with optical brighteners
    • A23L5/43—Addition of dyes or pigments, e.g. in combination with optical brighteners using naturally occurring organic dyes or pigments, their artificial duplicates or their derivatives
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
    • A23L5/00—Preparation or treatment of foods or foodstuffs, in general; Food or foodstuffs obtained thereby; Materials therefor
    • A23L5/40—Colouring or decolouring of foods
    • A23L5/42—Addition of dyes or pigments, e.g. in combination with optical brighteners
    • A23L5/43—Addition of dyes or pigments, e.g. in combination with optical brighteners using naturally occurring organic dyes or pigments, their artificial duplicates or their derivatives
    • A23L5/44—Addition of dyes or pigments, e.g. in combination with optical brighteners using naturally occurring organic dyes or pigments, their artificial duplicates or their derivatives using carotenoids or xanthophylls
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1617—Organic compounds, e.g. phospholipids, fats
    • A61K9/1623—Sugars or sugar alcohols, e.g. lactose; Derivatives thereof; Homeopathic globules
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1629—Organic macromolecular compounds
    • A61K9/1652—Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin

Definitions

  • the present invention relates to a process of preparing a hydrophobic or aerophilic powdered solid which is dispersible in water or in an aqueous solution (in the following referred to as a water dispersible solid) in the form of discrete microparticles.
  • the invention relates to a process of preparing water dispersible hydrophobic or aerophilic powdered colorants and biologically active solids.
  • bioavailability of biologically active powdered solids such as carotenoids and drugs, such as griseofulvin, ibuprofen, benzodiazepines and hormones, such as progesteron dispersed in an aqueous medium increases with decreasing particle size of the dispersed solid.
  • Published Japanese patent application No. 57-3861 discloses a process for preparation of a water-dispersible carotenoid formulation which comprises mixing and grinding a carotenoid with gum arabic in a dry state using a grinding apparatus, such as rotary ball mills, vibration ball mills, and hammer mills. Following grinding the solid product can be dissolved in water and the resulting solution can be converted into a powder by spray drying or freeze drying. A powder formulation having a carotenoid content of 1.5 percent by weight is obtained.
  • a disadvantage of this method is that the milled compounds may be damaged due to the increase of temperature during grinding or milling in the dry state because of the lack of efficient cooling equipment. Furthermore, it is difficult to prevent oxidation of the milled compounds during a dry grinding or milling operation.
  • Chimia 21,329 (1967), DE application No. 12 11 911 and DE publication No. 25 34 091 disclose methods of dissolving the active compound in a chlorinated organic solvent, emulsifying the solution in a gelatine/sucrose solution and extracting the solvent from the emulsion causing the active compound to crystallize in microcrystalline form.
  • a disadvantage of this method is that it is technically impossible to remove the organic solvent completely and the solvent is a potential hazard during the process and as residues in the final product.
  • DK-B-154.395 discloses a preparation, which has been prepared by dissolving a carotenoid or a retinoid in an organic solvent that is miscible with water at a temperature of between 50° and 200° C. optionally under pressure in less than 10 sec.
  • the resulting molecular-disperse solution is immediately mixed with an aqueous solution of a hydrocolloid, followed by an isolation of the colloid-disperse particles from the solvent to obtain a dry free flowing powder that can be dispersed in water.
  • This method is disadvantageous because of the use of organic solvents that require special equipment for collection of the solvents.
  • the concentration of the active compound will be relatively low in the final product, i.e., a maximum of about 20 percent by weight.
  • an aqueous dispersion of particles of hydrophobic/aerophilic solids can be prepared by mixing a hydrophobic/aerophilic solid with water in the presence of a wetting agent or tenside, such as lauryl sulfate or polysorbate. Without the use of a wetting agent milling is impossible, and without sufficient wetting the particles will agglomerate and the suspension will become too viscous for milling.
  • a wetting agent or tenside such as lauryl sulfate or polysorbate.
  • the object of the invention is to provide a process for preparing a hydrophobic/aerophilic solid that can be dispersed in water in the form of discrete microparticles without the use of oils, organic solvents and/or wetting agents or similar additives to form a microencapsulated product having a concentration of up to 71% of hydrophobic/aerophilic solid.
  • This object can be achieved by the process of the invention which process is characterized in that the solid is milled in an aqueous medium in the presence of a hydrocolloid in an amount of not less than about 10 percent by weight of the hydrophobic/aerophilic solid, to obtain a suspension containing suspended particles of an average particle size not exceeding 10 ⁇ m, and finely dividing and drying the suspension thus formed to obtain a powder.
  • hydrocolloid such as gelatine
  • the hydrocolloid provides sufficient wetting of the hydrophobic/aerophilic material to avoid agglomeration of the fine particles formed during the milling process.
  • the required minimum amount of the hydrocolloid to provide sufficient wetting of the solid is dependent on the specific solid and hydrocolloid and the presence of other excipients.
  • the hydrocolloid protects the new surfaces resulting from the milling of the relatively coarse particles of the hydrophobic/aerophilic material by creating a thin film that is intimately bound to the reactive new surfaces, thus preventing the particles to agglomerate due to hydrophobic interactions. Furthermore, the hydrocolloid reduces the surface tension and increases the dispersability of the final product.
  • the hydrocolloid protects the milled particles in both the liquid and the dried state, thus preventing recrystallisation and crystal growth of materials, such as low melting hormones, low melting lipids and other fat soluble materials.
  • microencapsulated products having a concentration of hydrophobic/aerophilic solid of up to 71% can be obtained.
  • the milling is preferably effected in a bead mill or any similar mill having cooling equipment for maintaining the temperature below a value at which the hydrofobic/aerophilic materials are decomposed and wherein the materials can be kept under a controlled atmosphere.
  • the hydrophobic/aerophilic solid is preferably added to an aqueous solution of a hydrocolloid that has been degassed by boiling under vacuum and preferably covered by N 2 or any other inert gas.
  • the mixture is then stirred at a temperature of between 0° C. and 100° C., the lower limit being determined by the temperature at which the hydrocolloid forms a gel and the upper limit being determined by the heat lability of the active compound.
  • Antioxidants may be added to the suspension.
  • the suspension is transferred to the mill which can be any type that is capable of milling the solid to a maximum particle size of 10 ⁇ m, is equipped with a cooling jacket and wherein the atmosphere can be controlled.
  • the temperature is between 0° C. and 100° C., preferably above 60° C. and the pressure is preferably between 0 and 5 bar.
  • the suspension may be pumped through the mill in a peristaltic pump or using a gear pump having a flow of from 50 to 1000 ml/min, preferably from 150 to 400 ml/min.
  • Solid hydrophobic/aerophilic materials that can be milled and encapsulated in the process according to the invention include carotenoids, such as ⁇ -carotene, annatto, bixin, norbixin, capsanthin, capsorubin, lycopene, ⁇ -apo-8'-carotenal, flavoxanthin, lutein, cryptoxanthin, rubixanthin, violaxanthin, rhodoxanthin, canthaxanthin, astaxanthin and citranaxanthin and derivatives thereof; natural colorants, such as curcumin, chlorophyll, carmine, etc.; and drugs, such as griseofulvin, ibuprofen, benzodiazepines, phenacetin and hormones.
  • carotenoids such as ⁇ -carotene, annatto, bixin, norbixin, capsanthin, capsorubin, lycopene, ⁇ -apo-8'-carotenal
  • Hydrocolloids that can be used in the process according to the invention include exudates, such as gum arabic, tragacanth, gum karaya, gum ghatti; extracts from seaweed, such as agar, alginate, carrageenan and furcellaran; extracts from plants, such as pectin and arabinogalactan; extracts from marine and terrestrial animals, such as gelatines and other proteinaceous hydrocolloids; flours from seeds, such as guar, locust bean, soya bean; proteins from seeds, such as soya bean protein; flours from cereals, such as starches and microcrystalline cellulose; biosynthetic or fermentation derived hydrocolloids, such as dextran, xanthan and curdlan; chemically modified hydrocolloids, such as cellulose derivatives, including methyl cellulose, and other derivatives, including modified starches and low methoxyl pectin; synthetic hydrocolloids, such as polyvinylpyrrolidon, carboxyviny
  • the aqueous medium can optionally further contain excipients in an amount of up to 70 percent by weight of the suspension, such as a dissolved carbohydrate, such as sorbitol and sucrose, and/or an antioxidant or an oil containing an antioxidant.
  • excipients in an amount of up to 70 percent by weight of the suspension, such as a dissolved carbohydrate, such as sorbitol and sucrose, and/or an antioxidant or an oil containing an antioxidant.
  • the resulting suspension is finely divided and dried using any combination of conventional methods, such as spray cooling, spray drying, modified spray drying or sheet drying and crushing, etc.
  • hydrocolloid used in the milling of a hydrophobic/aerophilic solid can act as a matrix material in a subsequent encapsulation process. Such processes will be described in the following.
  • a suspension containing a hydrocolloid is preferably sprayed using an atomizing nozzle or an atomizing wheel at a temperature higher than the gelling/melting point, i.e. from about 38° to about 95° C. and at a viscosity of preferably between 50 and 300 mPa.s in a spraying chamber, wherein the temperature is from 0° to about 40° C., thereby forming microcapsules of gelatinized hydrocolloid.
  • a powdery spraying excipient is preferably blown into the spraying chamber in order to prevent agglomeration of the gelatinized microcapsules and to prevent adherence to the chamber wall.
  • the spraying excipient is preferably supplied in an amount of from 5 to 50 percent by weight based on the weight of the final product.
  • microcapsules are transferred a fluidized bed, wherein they may be dried to a residual water content of between 0 and 10% (preferably from 2 to 5%) and in which excessive spraying excipient is separated.
  • the drying air temperature is preferably from about 0° to about 60° C.
  • the modified spray drying process differs from the spray cooling process in that the temperature in the spraying chamber is high, preferably between 50° and 95° C.
  • the suspension is preferably sprayed at a temperature of from 5° to 99° C. and at a viscosity of from 50 to 300 mPa.s using an atomizing nozzle or an atomizing wheel in a spraying chamber, wherein the temperature is from 50° to 95° C.
  • a powdery spraying excipient may be blown into the spraying chamber in order to prevent agglomeration of the formed microcapsules and to prevent adherence to the chamber wall.
  • the spraying excipient is preferably supplied in an amount of from 5 to 50 percent by weight based on the weight of the final product.
  • the powdered microcapsules may be transferred to a fluidized bed, wherein they may be dried to a residual water content of between 0 and 10% (preferably from 2 to 5%) and excessive spraying excipient is separated.
  • the drying air temperature is preferable from about 0° to about 60° C.
  • spray drying and modified spray drying processes the following spraying excipients may be used: starches, modified starches, tricalcium phosphate, lactose, mannitol, ethyl cellulose, coagulated albumin, hardened gelatine, casein, stearat-Ca, stearat-Na, metal soaps, hydrogenated ricinus oil, polyoxide, talcum, waxes, and silicates.
  • the suspension is preferably dried in a thin layer to form a solidified suspension which subsequently may be ground into a powder.
  • the suspension may be emulsified in an oil, washed and dried/spray dried or extruded, drum dried and crushed or treated by any combination of known methods of finely dividing and drying or drying and finely dividing.
  • Microencapsulated ⁇ -carotene may be a constituent of vitamin tablets.
  • hydrocolloid protection of microparticles of hydrophobic/aerophilic compounds is an improved performance when preparing tablets from such compounds.
  • an antioxidant in the suspension when the active compound is sensitive to oxygen.
  • the antioxidant can be water soluble or water insoluble and can be incorporated during the milling process or in a subsequent emulsification process.
  • the dispersability of the microencapsulated product is evaluated visually after the addition of 0.2 g of microencapsulated product to 200 ml of water having a temperature of 40°-45° C. in a beaker.
  • the dispersability is satisfactory when the microencapsulated particles are immediately wetted and a uniform dispersion is formed after 2 minutes of stirring. When viewed in a light microscope in transparency the dispersion consists of predominantly discrete particles.
  • the amount of hydrophobic/aerophilic solid is up to 71 percent by weight of the microencapsulated product.
  • the microcapsules prepared by the process described above can be used in pharmaceutical compositions, feeds and foodstuffs.
  • the milled suspension was transferred in a N 2 -atmosphere to a degassed aqueous solution of 1300 g of gelatine and 2044 g of sucrose, wherein 9.5 g of ascorbyl palmitate and 14.3 g of a mixture of ⁇ -, ⁇ -, and ⁇ -tocopherol had been emulsified. After being thoroughly mixed the resulting suspension was spray cooled in a conventional manner.
  • the milled suspension was transferred to a degassed aqueous solution of 184 g of gelatine and 484 g of sucrose in a N 2 -atmosphere, wherein 7.9 g of a mixture of ⁇ -, ⁇ -, and ⁇ -tocopherol had been emulsified. After being thoroughly mixed the resulting suspension was spray cooled in a conventional manner.
  • ⁇ -carotene 500 g was added to a solution of 146 g of 240 Bloom gelatine and 50 g of Na-ascorbat in 1000 g of water having a temperature of 65° C.
  • the suspension was milled in a bead mill, DynoMill type KDL, during 1 hour of recirculation.
  • 7.1 g of a mixture of ⁇ -, ⁇ -, and ⁇ -tocopherol had been emulsified. After being thoroughly mixed the resulting suspension was spray cooled in a conventional manner.
  • the milled suspension was transferred to a degassed aqueous solution of 592 g of 30 Bloom gelatine and 558 g of sucrose in a N 2 -atmosphere, wherein a mixture of 117 g of coconut oil and 0.7 g of a mixture of ⁇ -, ⁇ -, and ⁇ -tocopherol had been emulsified. After being thoroughly mixed the resulting suspension was subjected to a modified spray drying.
  • the final product contained 4.4 percent by weight of canthaxanthin.
  • Astaxanthin 25 g was added to a solution of 14.5 g of 106 Bloom gelatine and 2.5 g of Na-ascorbat in 1500 g of water having a temperature of 65° C.
  • the suspension was milled in a bead mill, DynoMill type KDL, during 1 hour.
  • the milled suspension was transferred to an aqueous solution of 153 g of 240 Bloom gelatine and 153 g of sucrose, wherein 0.5 g of ascorbyl palmitate and 2.0 g of BHT and 10.0 g of ethoxyquin had been emulsified. After being thoroughly mixed the resulting suspension was spray cooled in a conventional manner.
  • the final product contained 4.5 percent by weight of astaxanthin.
  • ⁇ -carotene 500 g was added to a solution of 250 g of gum arabic and 50 g of Na-ascorbat in 1750 g of water having a temperature of 65° C.
  • the suspension was milled in a bead mill, DynoMill type KDL, during 1 hour of recirculation.
  • the milled suspension was transferred to an aqueous solution of 916 g of gum arabic and 780 g of sucrose, wherein 7.4 g of a mixture of ⁇ -, ⁇ -, and ⁇ -tocopherol had been emulsified. After being thoroughly mixed the resulting suspension was spray cooled in a conventional manner.
  • ⁇ -carotene 500 g was added to a solution of 200 g of Methocel® E5 and 50 g of Na-ascorbat in 2000 g of water having a temperature of 65° C.
  • the suspension was milled in a bead mill, DynoMill type KDL, during 1 hour of recirculation.
  • the milled suspension was transferred to an aqueous solution of 323 g of Methocel® E5 and 1224 g of sucrose, wherein 7.6 g of a mixture of ⁇ -, ⁇ -, and ⁇ -tocopherol had been emulsified.
  • the resulting suspension was subjected to a modified spray drying process in a conventional manner.
  • 500 g of ⁇ -carotene was added to a solution of 500 g of Capsul® 50 g and of Na-ascorbat in 1500 g of water having a temperature of 65° C.
  • the suspension was milled in a bead mill, DynoMill type KDL, during 1 hour of recirculation.
  • the milled suspension was transferred to an aqueous solution of 665 g of Capsul® and 777 g of sucrose, wherein 7.2 g of a mixture of ⁇ -, ⁇ -, and ⁇ -tocopherol had been emulsified.
  • the resulting suspension was subjected to a modified spray drying process in a conventional manner.
  • ⁇ -carotene 500 g was added to a solution of 292 g of 240 Bloom gelatine in 1400 g of water having a temperature of 65° C.
  • the suspension was milled in a bead mill, DynoMill type KDL, during 1 hour of recirculation.
  • the milled suspension was transferred to an aqueous solution of 1132 g of 240 Bloom gelatine and 1298 g of sucrose, wherein 7.4 g of a mixture of ⁇ -, ⁇ -, and ⁇ -tocopherol had been emulsified. After being thoroughly mixed the resulting suspension was spray cooled in a conventional manner.
  • Ibuprofen 250 g was added to a solution of 146 g of 240 Bloom gelatine in 700 g of water having a temperature of 65° C.
  • the suspension was milled in a bead mill, DynoMill type KDL, during 1 hour of recirculation.
  • the milled suspension was transferred to an aqueous solution of 566 g of 240 Bloom gelatine and 649 g of sucrose. After being thoroughly mixed the resulting suspension was spray cooled in a conventional manner.
  • the final product contained 12.9 percent by weight of ibuprofen.
  • 300 g of Curcumin crystals was added to a solution of 300 g of low bloom gelatine and 300 g of sucrose in 900 g of water having a temperature of 65° C.
  • the suspension was milled in a bead mill, DynoMill type KDL, during 1 hour of recirculation.
  • the milled suspension was transferred to a solution of 750 g of sucrose in 300 g of water. After being thoroughly mixed the resulting suspension was subjected to a modified spray drying process.
  • the final product contained 26.0 percent by weight of curcumin.

Abstract

A process for producing hydrophobic or aerophobic solids having a particle size not exceeding 10 μm, which solids can be dispersed in water in the form of discrete microparticles. In the process the solids are milled in an aqueous medium in the presence of a hydrocolloid to obtain a suspension containing suspended particles having an average particle size not exceeding 10 μm. The suspension is then finely divided and dried to form a powder.

Description

This application is a continuation of application Ser. No. 855,641, filed as PCT/DK90/00278, Nov. 2, 1990 now abandoned.
BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates to a process of preparing a hydrophobic or aerophilic powdered solid which is dispersible in water or in an aqueous solution (in the following referred to as a water dispersible solid) in the form of discrete microparticles.
2. The Prior Art
More specifically the invention relates to a process of preparing water dispersible hydrophobic or aerophilic powdered colorants and biologically active solids.
It is well known that the coloring effect of a colorant or pigment dispersed in an aqueous medium, increases with decreasing particle size of the colorant or pigment and that the color intensity of the dispersion increases with increasing dispersability.
It is also well known that the bioavailability of biologically active powdered solids, such as carotenoids and drugs, such as griseofulvin, ibuprofen, benzodiazepines and hormones, such as progesteron dispersed in an aqueous medium increases with decreasing particle size of the dispersed solid.
Therefore, there is a need for providing water dispersible hydrophobic or aerophilic solids of a small particle size, e.g., a particle size not exceeding 10 μm, and more preferably not exceeding 2 μm.
Various methods of reducing the particle size of hydrophobic/aerophilic compounds to a maximum average of 10 μm have been disclosed. It is known to mill β-carotene together with edible oil in a colloid mill (Chimia 21, 329 (67)). Using this method it is possible to achieve a β-carotene content in the oil of about 30%.
Published Japanese patent application No. 57-3861 discloses a process for preparation of a water-dispersible carotenoid formulation which comprises mixing and grinding a carotenoid with gum arabic in a dry state using a grinding apparatus, such as rotary ball mills, vibration ball mills, and hammer mills. Following grinding the solid product can be dissolved in water and the resulting solution can be converted into a powder by spray drying or freeze drying. A powder formulation having a carotenoid content of 1.5 percent by weight is obtained. A disadvantage of this method is that the milled compounds may be damaged due to the increase of temperature during grinding or milling in the dry state because of the lack of efficient cooling equipment. Furthermore, it is difficult to prevent oxidation of the milled compounds during a dry grinding or milling operation.
Moreover, Chimia 21,329 (1967), DE application No. 12 11 911 and DE publication No. 25 34 091 disclose methods of dissolving the active compound in a chlorinated organic solvent, emulsifying the solution in a gelatine/sucrose solution and extracting the solvent from the emulsion causing the active compound to crystallize in microcrystalline form. A disadvantage of this method is that it is technically impossible to remove the organic solvent completely and the solvent is a potential hazard during the process and as residues in the final product.
DK-B-154.395 discloses a preparation, which has been prepared by dissolving a carotenoid or a retinoid in an organic solvent that is miscible with water at a temperature of between 50° and 200° C. optionally under pressure in less than 10 sec. The resulting molecular-disperse solution is immediately mixed with an aqueous solution of a hydrocolloid, followed by an isolation of the colloid-disperse particles from the solvent to obtain a dry free flowing powder that can be dispersed in water. This method is disadvantageous because of the use of organic solvents that require special equipment for collection of the solvents. Furthermore, the concentration of the active compound will be relatively low in the final product, i.e., a maximum of about 20 percent by weight. Furthermore, it is stated that it has not been possible to mill hydrophobic solids, such as β-carotene in water or in an aqueous system to obtain the desired particle size without damage to the active compounds.
Research Disclosure (RD) 17064, June 1978, describes a method of preparing stable carotenoid colorants, wherein the carotenoids are milled in ball mills in an aqueous or oily medium in the presence of a protective colloid and a carrier, such as gelatine, and an ionic emulgator. The milling in the aqueous medium is followed by a spray drying process resulting in a water dispersible colorant having a carotenoid content of about 10%. However, the ionic emulgator will be present in the final product, which is undesirable especially when the colorant is to be used in food products.
It is well known that an aqueous dispersion of particles of hydrophobic/aerophilic solids can be prepared by mixing a hydrophobic/aerophilic solid with water in the presence of a wetting agent or tenside, such as lauryl sulfate or polysorbate. Without the use of a wetting agent milling is impossible, and without sufficient wetting the particles will agglomerate and the suspension will become too viscous for milling.
SUMMARY OF THE INVENTION
The object of the invention is to provide a process for preparing a hydrophobic/aerophilic solid that can be dispersed in water in the form of discrete microparticles without the use of oils, organic solvents and/or wetting agents or similar additives to form a microencapsulated product having a concentration of up to 71% of hydrophobic/aerophilic solid.
This object can be achieved by the process of the invention which process is characterized in that the solid is milled in an aqueous medium in the presence of a hydrocolloid in an amount of not less than about 10 percent by weight of the hydrophobic/aerophilic solid, to obtain a suspension containing suspended particles of an average particle size not exceeding 10 μm, and finely dividing and drying the suspension thus formed to obtain a powder.
It is further assumed that the hydrocolloid, such as gelatine, provides sufficient wetting of the hydrophobic/aerophilic material to avoid agglomeration of the fine particles formed during the milling process. The required minimum amount of the hydrocolloid to provide sufficient wetting of the solid is dependent on the specific solid and hydrocolloid and the presence of other excipients.
It is assumed that the hydrocolloid protects the new surfaces resulting from the milling of the relatively coarse particles of the hydrophobic/aerophilic material by creating a thin film that is intimately bound to the reactive new surfaces, thus preventing the particles to agglomerate due to hydrophobic interactions. Furthermore, the hydrocolloid reduces the surface tension and increases the dispersability of the final product.
Moreover, the hydrocolloid protects the milled particles in both the liquid and the dried state, thus preventing recrystallisation and crystal growth of materials, such as low melting hormones, low melting lipids and other fat soluble materials.
Surprisingly, it has been found that by using the process of the invention microencapsulated products having a concentration of hydrophobic/aerophilic solid of up to 71% can be obtained.
The milling is preferably effected in a bead mill or any similar mill having cooling equipment for maintaining the temperature below a value at which the hydrofobic/aerophilic materials are decomposed and wherein the materials can be kept under a controlled atmosphere.
In a preferred embodiment of the process according to the invention the hydrophobic/aerophilic solid is preferably added to an aqueous solution of a hydrocolloid that has been degassed by boiling under vacuum and preferably covered by N2 or any other inert gas. The mixture is then stirred at a temperature of between 0° C. and 100° C., the lower limit being determined by the temperature at which the hydrocolloid forms a gel and the upper limit being determined by the heat lability of the active compound. Antioxidants may be added to the suspension.
The suspension is transferred to the mill which can be any type that is capable of milling the solid to a maximum particle size of 10 μm, is equipped with a cooling jacket and wherein the atmosphere can be controlled. During the milling the temperature is between 0° C. and 100° C., preferably above 60° C. and the pressure is preferably between 0 and 5 bar. The suspension may be pumped through the mill in a peristaltic pump or using a gear pump having a flow of from 50 to 1000 ml/min, preferably from 150 to 400 ml/min.
Solid hydrophobic/aerophilic materials that can be milled and encapsulated in the process according to the invention include carotenoids, such as β-carotene, annatto, bixin, norbixin, capsanthin, capsorubin, lycopene, β-apo-8'-carotenal, flavoxanthin, lutein, cryptoxanthin, rubixanthin, violaxanthin, rhodoxanthin, canthaxanthin, astaxanthin and citranaxanthin and derivatives thereof; natural colorants, such as curcumin, chlorophyll, carmine, etc.; and drugs, such as griseofulvin, ibuprofen, benzodiazepines, phenacetin and hormones.
Hydrocolloids that can be used in the process according to the invention include exudates, such as gum arabic, tragacanth, gum karaya, gum ghatti; extracts from seaweed, such as agar, alginate, carrageenan and furcellaran; extracts from plants, such as pectin and arabinogalactan; extracts from marine and terrestrial animals, such as gelatines and other proteinaceous hydrocolloids; flours from seeds, such as guar, locust bean, soya bean; proteins from seeds, such as soya bean protein; flours from cereals, such as starches and microcrystalline cellulose; biosynthetic or fermentation derived hydrocolloids, such as dextran, xanthan and curdlan; chemically modified hydrocolloids, such as cellulose derivatives, including methyl cellulose, and other derivatives, including modified starches and low methoxyl pectin; synthetic hydrocolloids, such as polyvinylpyrrolidon, carboxyvinyl polymers, etc.
The aqueous medium can optionally further contain excipients in an amount of up to 70 percent by weight of the suspension, such as a dissolved carbohydrate, such as sorbitol and sucrose, and/or an antioxidant or an oil containing an antioxidant.
The resulting suspension is finely divided and dried using any combination of conventional methods, such as spray cooling, spray drying, modified spray drying or sheet drying and crushing, etc.
Another advantage of the process according to the invention is that the hydrocolloid used in the milling of a hydrophobic/aerophilic solid can act as a matrix material in a subsequent encapsulation process. Such processes will be described in the following.
SPRAY COOLING
In a spray cooling process a suspension containing a hydrocolloid is preferably sprayed using an atomizing nozzle or an atomizing wheel at a temperature higher than the gelling/melting point, i.e. from about 38° to about 95° C. and at a viscosity of preferably between 50 and 300 mPa.s in a spraying chamber, wherein the temperature is from 0° to about 40° C., thereby forming microcapsules of gelatinized hydrocolloid.
A powdery spraying excipient is preferably blown into the spraying chamber in order to prevent agglomeration of the gelatinized microcapsules and to prevent adherence to the chamber wall. The spraying excipient is preferably supplied in an amount of from 5 to 50 percent by weight based on the weight of the final product.
The microcapsules are transferred a fluidized bed, wherein they may be dried to a residual water content of between 0 and 10% (preferably from 2 to 5%) and in which excessive spraying excipient is separated. The drying air temperature is preferably from about 0° to about 60° C.
MODIFIED SPRAY DRYING
The modified spray drying process differs from the spray cooling process in that the temperature in the spraying chamber is high, preferably between 50° and 95° C.
In the modified spray drying process the suspension is preferably sprayed at a temperature of from 5° to 99° C. and at a viscosity of from 50 to 300 mPa.s using an atomizing nozzle or an atomizing wheel in a spraying chamber, wherein the temperature is from 50° to 95° C.
A powdery spraying excipient may be blown into the spraying chamber in order to prevent agglomeration of the formed microcapsules and to prevent adherence to the chamber wall. The spraying excipient is preferably supplied in an amount of from 5 to 50 percent by weight based on the weight of the final product.
The powdered microcapsules may be transferred to a fluidized bed, wherein they may be dried to a residual water content of between 0 and 10% (preferably from 2 to 5%) and excessive spraying excipient is separated. The drying air temperature is preferable from about 0° to about 60° C.
In the spray cooling, spray drying and modified spray drying processes the following spraying excipients may be used: starches, modified starches, tricalcium phosphate, lactose, mannitol, ethyl cellulose, coagulated albumin, hardened gelatine, casein, stearat-Ca, stearat-Na, metal soaps, hydrogenated ricinus oil, polyoxide, talcum, waxes, and silicates.
In a sheet drying process the suspension is preferably dried in a thin layer to form a solidified suspension which subsequently may be ground into a powder. Alternatively, the suspension may be emulsified in an oil, washed and dried/spray dried or extruded, drum dried and crushed or treated by any combination of known methods of finely dividing and drying or drying and finely dividing.
Microencapsulated β-carotene may be a constituent of vitamin tablets. However, because of the relatively low concentration of β-carotene in microcapsules prepared using the known techniques, it is necessary to formulate the vitamin tablets with a relatively large amount of β-carotene microcapsules resulting in bulky tablets. This obstacle is overcome when tablets are formulated with microcapsules having a high β-carotene content that are prepared according to the invention.
Another advantage of the hydrocolloid protection of microparticles of hydrophobic/aerophilic compounds, such as phenacetin, is an improved performance when preparing tablets from such compounds.
It is preferred to include an antioxidant in the suspension when the active compound is sensitive to oxygen. The antioxidant can be water soluble or water insoluble and can be incorporated during the milling process or in a subsequent emulsification process.
The dispersability of the microencapsulated product is evaluated visually after the addition of 0.2 g of microencapsulated product to 200 ml of water having a temperature of 40°-45° C. in a beaker. The dispersability is satisfactory when the microencapsulated particles are immediately wetted and a uniform dispersion is formed after 2 minutes of stirring. When viewed in a light microscope in transparency the dispersion consists of predominantly discrete particles.
In the microencapsulated product prepared according to the above process containing a hydrophobic/aerophilic solic having a maximum average particle size not exceeding 10 μm and which can be dispersed in water in the form of discrete microparticles, the amount of hydrophobic/aerophilic solid is up to 71 percent by weight of the microencapsulated product. The microcapsules prepared by the process described above can be used in pharmaceutical compositions, feeds and foodstuffs.
EXAMPLE 1
1000 g of β-carotene was added in a N2 -atmosphere to a solution of 584 g of 240 Bloom gelatine and 100 g of Na-ascorbat in 2800 g of water having a temperature of 65° C. Before the addition of β-carotene the solution had been degassed using a vacuum and the pressure had been brought to equilibrium with N2. When the β-carotene crystals were sufficiently wetted, the suspension was milled in a bead mill, DynoMill type KDL, during 1 hour of recirculation. The milled suspension was transferred in a N2 -atmosphere to a degassed aqueous solution of 1300 g of gelatine and 2044 g of sucrose, wherein 9.5 g of ascorbyl palmitate and 14.3 g of a mixture of α-, β-, and γ-tocopherol had been emulsified. After being thoroughly mixed the resulting suspension was spray cooled in a conventional manner.
The following intervals of product characteristics for four products were obtained:
______________________________________                                    
carotene content: 13.2-13.8                                               
                           percent by weight                              
extractable β-carotene:                                              
                  0.3-0.8  percent by weight                              
absorption ratio A.sub.452 nm :A.sub.483 nm :                             
                  1.16                                                    
absorption ratio A.sub.452 nm :A.sub.340 nm :                             
                  14.7-15.2                                               
stability after 6 months at 22° C.:                                
                  100%     of original β-                            
                           carotene content                               
______________________________________
The visual dispersability test was satisfactory.
EXAMPLE 2
600 g of β-carotene was added in a N2 -atmosphere to a solution of 350 g of 240 Bloom gelatine and 60 g of Na-ascorbat in 1500 g of water having a temperature of 65° C. Before the addition of β-carotene the solution had been degassed using a vacuum and the pressure had been brought to equilibrium with N2. When the β-carotene crystals were sufficiently wetted, the suspension was milled in a bead mill, DynoMill type KDL, during 1 hour of recirculation. The milled suspension was transferred to a degassed aqueous solution of 184 g of gelatine and 484 g of sucrose in a N2 -atmosphere, wherein 7.9 g of a mixture of α-, β-, and γ-tocopherol had been emulsified. After being thoroughly mixed the resulting suspension was spray cooled in a conventional manner.
The following product characteristics were obtained:
______________________________________                                    
carotene content:  16.9    percent by weight                              
extractable β-carotene:                                              
                   0.4     percent by weight                              
absorption ratio A.sub.452 nm :A.sub.483 nm :                             
                   1.16                                                   
absorption ratio A.sub.452 nm :A.sub.340 nm :                             
                   15.4                                                   
stability after 3 months at 22° C.:                                
                   98.7%   of original β-                            
                           carotene content                               
______________________________________
The visual dispersability test was satisfactory.
EXAMPLE 3
500 g of β-carotene was added to a solution of 146 g of 240 Bloom gelatine and 50 g of Na-ascorbat in 1000 g of water having a temperature of 65° C. When the β-carotene crystals were sufficiently wetted, the suspension was milled in a bead mill, DynoMill type KDL, during 1 hour of recirculation. In the milled suspension 7.1 g of a mixture of α-, β-, and γ-tocopherol had been emulsified. After being thoroughly mixed the resulting suspension was spray cooled in a conventional manner.
The following product characteristics were obtained:
______________________________________                                    
carotene content:  42.5   percent by weight                               
absorption ratio A.sub.452 nm :A.sub.483 nm :                             
                   1.19                                                   
absorption ratio A.sub.452 nm :A.sub.340 nm :                             
                   10.3                                                   
______________________________________
The visual dispersability test was satisfactory.
EXAMPLE 4
360 g of β-carotene was added to a solution of 210 g of low Bloom gelatine and 36 g of Na-ascorbat in 935 g of water having a temperature of 65° C. When the β-carotene crystals were sufficiently wetted, the suspension was milled in a bead mill, DynoMill type KDL, during 1 hour of recirculation. The milled suspension was transferred to an aqueous solution of 648 g of high Bloom gelatine and 556 g of sucrose, wherein a mixture of 151 g of coconut oil and 0.9 g of a mixture of α-, β-, and γ-tocopherol had been emulsified. After being thoroughly mixed the resulting suspension was spray cooled in a conventional manner.
The following product characteristics were obtained:
______________________________________                                    
carotene content:  11.3    percent by weight                              
extractable β-carotene:                                              
                   0.1     percent by weight                              
absorption ratio A.sub.452 nm :A.sub.483 nm :                             
                   1.16                                                   
absorption ratio A.sub.452 nm :A.sub.340 nm :                             
                   14.8                                                   
stability after 3 months at 22° C.:                                
                   96.5%   of original β-                            
                           carotene content                               
______________________________________
The visual dispersability test was satisfactory.
EXAMPLE 5
600 g of β-carotene was added in a N2 -atmosphere to a solution of 350 g of 70 Bloom gelatine and 60 g of Na-ascorbat in 1500 g of water having a temperature of 65° C. Before the addition of β-carotene the solution had been degassed using a vacuum and the pressure had been brought to equilibrium with N2. When the β-carotene crystals were sufficiently wetted, the suspension was milled in a bead mill, DynoMill type KDL, during 1 hour of recirculation. The milled suspension was transferred to a degassed aqueous solution of 592 g of 30 Bloom gelatine and 558 g of sucrose in a N2 -atmosphere, wherein a mixture of 117 g of coconut oil and 0.7 g of a mixture of α-, β-, and γ-tocopherol had been emulsified. After being thoroughly mixed the resulting suspension was subjected to a modified spray drying.
The following product characteristics were obtained:
______________________________________                                    
carotene content:  11.4    percent by weight                              
extractable β-carotene:                                              
                   0.7     percent by weight                              
absorption ratio A.sub.452 nm :A.sub.483 nm :                             
                   1.16                                                   
absorption ratio A.sub.452 nm :A.sub.340 nm :                             
                   14.4                                                   
stability after 3 months at 22° C.:                                
                   95.1%   of original β-                            
                           carotene content                               
______________________________________
The visual dispersability test was satisfactory.
EXAMPLE 6
25 g of Canthaxanthin was added to a solution of 14.5 g of 106 Bloom gelatine and 2.5 g of Na-ascorbat in 70 g of water having a temperature of 65° C. When the cantaxanthin crystals were sufficiently wetted, the suspension was milled in a bead mill, DynoMill type KDL, during 1 hour. The milled suspension was transferred to an aqueous solution of 153 g of 240 Bloom gelatine and 153 g of sucrose, wherein 0.5 g of ascorbyl palmitate and 2.0 g of BHT and 10.0 g of ethoxyquin had been emulsified. After being thoroughly mixed the resulting suspension was spray cooled in a conventional manner.
The final product contained 4.4 percent by weight of canthaxanthin.
The visual dispersability test was satisfactory.
EXAMPLE 7
25 g of Astaxanthin was added to a solution of 14.5 g of 106 Bloom gelatine and 2.5 g of Na-ascorbat in 1500 g of water having a temperature of 65° C. When the astaxanthin crystals were sufficiently wetted, the suspension was milled in a bead mill, DynoMill type KDL, during 1 hour. The milled suspension was transferred to an aqueous solution of 153 g of 240 Bloom gelatine and 153 g of sucrose, wherein 0.5 g of ascorbyl palmitate and 2.0 g of BHT and 10.0 g of ethoxyquin had been emulsified. After being thoroughly mixed the resulting suspension was spray cooled in a conventional manner.
The final product contained 4.5 percent by weight of astaxanthin.
The visual dispersability test was satisfactory.
EXAMPLE 8
500 g of β-carotene was added to a solution of 250 g of gum arabic and 50 g of Na-ascorbat in 1750 g of water having a temperature of 65° C. When the β-carotene crystals were sufficiently wetted, the suspension was milled in a bead mill, DynoMill type KDL, during 1 hour of recirculation. The milled suspension was transferred to an aqueous solution of 916 g of gum arabic and 780 g of sucrose, wherein 7.4 g of a mixture of α-, β-, and γ-tocopherol had been emulsified. After being thoroughly mixed the resulting suspension was spray cooled in a conventional manner.
The following product characteristics were obtained:
______________________________________                                    
carotene content:  8.9    percent by weight                               
absorption ratio A.sub.452 nm :A.sub.483 nm :                             
                   1.16                                                   
absorption ratio A.sub.452 nm :A.sub.340 nm :                             
                   14.2                                                   
______________________________________
The visual dispersability test was satisfactory.
EXAMPLE 9
500 g of β-carotene was added to a solution of 200 g of Methocel® E5 and 50 g of Na-ascorbat in 2000 g of water having a temperature of 65° C. When the β-carotene crystals were sufficiently wetted, the suspension was milled in a bead mill, DynoMill type KDL, during 1 hour of recirculation. The milled suspension was transferred to an aqueous solution of 323 g of Methocel® E5 and 1224 g of sucrose, wherein 7.6 g of a mixture of α-, β-, and γ-tocopherol had been emulsified. After being thoroughly mixed the resulting suspension was subjected to a modified spray drying process in a conventional manner.
The following product characteristics were obtained:
______________________________________                                    
carotene content:  4.0    percent by weight                               
absorption ratio A.sub.452 nm :A.sub.483 nm :                             
                   1.19                                                   
absorption ratio A.sub.452 nm :A.sub.340 nm :                             
                   10.0                                                   
______________________________________
The visual dispersability test was satisfactory.
EXAMPLE 10
500 g of β-carotene was added to a solution of 500 g of Capsul® 50 g and of Na-ascorbat in 1500 g of water having a temperature of 65° C. When the β-carotene crystals were sufficiently wetted, the suspension was milled in a bead mill, DynoMill type KDL, during 1 hour of recirculation. The milled suspension was transferred to an aqueous solution of 665 g of Capsul® and 777 g of sucrose, wherein 7.2 g of a mixture of α-, β-, and γ-tocopherol had been emulsified. After being thoroughly mixed the resulting suspension was subjected to a modified spray drying process in a conventional manner.
The following product characteristics were obtained:
______________________________________                                    
carotene content:  9.9    percent by weight                               
absorption ratio A.sub.452 nm :A.sub.483 nm :                             
                   1.16                                                   
absorption ratio A.sub.452 nm :A.sub.340 nm :                             
                   13.6                                                   
______________________________________
The visual dispersability test was satisfactory.
EXAMPLE 11
500 g of β-carotene was added to a solution of 292 g of 240 Bloom gelatine in 1400 g of water having a temperature of 65° C. When the β-carotene crystals were sufficiently wetted, the suspension was milled in a bead mill, DynoMill type KDL, during 1 hour of recirculation. The milled suspension was transferred to an aqueous solution of 1132 g of 240 Bloom gelatine and 1298 g of sucrose, wherein 7.4 g of a mixture of α-, β-, and γ-tocopherol had been emulsified. After being thoroughly mixed the resulting suspension was spray cooled in a conventional manner.
The following product characteristics were obtained:
______________________________________                                    
carotene content:  10.5   percent by weight                               
extractable β-carotene:                                              
                   0.3    percent by weight                               
absorption ratio A.sub.452 nm :A.sub.483 nm :                             
                   1.17                                                   
absorption ratio A.sub.452 nm :A.sub.340 nm :                             
                   14.6                                                   
______________________________________
The visual dispersability test was satisfactory.
EXAMPLE 12
250 g of Ibuprofen was added to a solution of 146 g of 240 Bloom gelatine in 700 g of water having a temperature of 65° C. When the ibuprofen crystals were sufficiently wetted, the suspension was milled in a bead mill, DynoMill type KDL, during 1 hour of recirculation. The milled suspension was transferred to an aqueous solution of 566 g of 240 Bloom gelatine and 649 g of sucrose. After being thoroughly mixed the resulting suspension was spray cooled in a conventional manner.
The final product contained 12.9 percent by weight of ibuprofen.
EXAMPLE 13
300 g of Curcumin crystals was added to a solution of 300 g of low bloom gelatine and 300 g of sucrose in 900 g of water having a temperature of 65° C. When the curcumine crystals were sufficiently wetted, the suspension was milled in a bead mill, DynoMill type KDL, during 1 hour of recirculation. The milled suspension was transferred to a solution of 750 g of sucrose in 300 g of water. After being thoroughly mixed the resulting suspension was subjected to a modified spray drying process.
The final product contained 26.0 percent by weight of curcumin.

Claims (18)

We claim:
1. A process of preparing a hydrophobic solid powder which is a carotenoid or a natural colorant and which can be dispersed in water in the form of discrete microparticles, comprising the steps of:
a) providing a hydrophobic solid,
b) adding the solid to an aqueous solution of a hydrocolloid comprising not less than about 10 percent by weight of said solid to obtain a mixture, which hydrocolloid is gelatine, gum arabic, soy bean protein or modified starch or mixtures thereof,
c) stirring the mixture at a temperature between 0° C. and 100° C. to form a first aqueous suspension,
d) transferring the first aqueous suspension to a mill having cooling equipment for maintaining the temperature below the decomposition temperature of said solid,
e) wet grinding said solid which is present in said aqueous suspension in said mill at a temperature between 0° C. and 100° C. to obtain a second aqueous suspension wherein the maximum particle size of the solid is 10 μm, and
f) finely dividing and drying said second aqueous suspension to obtain a powder.
2. A process according to claim 1, wherein the suspension containing suspended particles is finely divided and dried by spray cooling, conventional spray drying or modified spray drying.
3. A process according to claim 2, wherein the suspension containing suspended particles is finely divided and dried by spray cooling, conventional spray drying or modified spray drying.
4. A process according to claim 1, wherein the carotenoid is β-carotene, β-apo-8'-carotenal, canthaxanthin, and/or astaxanthin.
5. A process according to claim 1, wherein the natural colorant is curcumin.
6. A process according to claim 1, wherein the suspension contains a carbohydrate, in an amount of up to 70 percent by weight of the suspension.
7. A process according to claim 6, wherein the carbohydrate is sucrose.
8. A process according to claim 1, wherein the suspension further contains an antioxidant.
9. A process according to claim 1, wherein the hydrophobic solid is used in an amount which is sufficient to provide a microencapsulated product having a concentration of up to 71 percent by weight of hydrophobic solid.
10. A process of preparing an aerophilic solid powder which is a carotenoid or a natural colorant and which can be dispersed in water in the form of discrete microparticles, comprising the steps of:
a) providing an aerophilic solid,
b) adding the solid to an aqueous solution of a hydrocolloid comprising not less than about 10 percent by weight of said solid to obtain a mixture, which hydrocolloid is gelatine, gum arabic, soy bean protein or modified starch or mixtures thereof,
c) stirring the mixture at a temperature between 0° C. and 100° C. to form a first aqueous suspension,
d) transferring the first aqueous suspension to a mill having cooling equipment for maintaining the temperature below the decomposition temperature of said solid,
e) wet grinding said solid which is present in said aqueous suspension in said mill at a temperature between 0° C. and 100° C. to obtain a second aqueous suspension wherein the maximum particle size of the solid is 10 μm, and
f) finely dividing and drying said second aqueous suspension to obtain a powder.
11. A process according to claim 10, wherein the suspension containing suspended particles is finely divided and dried by spray cooling or spray drying.
12. A process according to claim 1, wherein the suspension containing suspended particles is finely divided and dried by spray cooling or spray drying.
13. A process according to claim 11, wherein the carotenoid is β-carotene, β-apo-8'-carotenal, canthaxanthin, and/or astaxanthin.
14. A process according to claim 11, wherein the natural colorant is curcumin, chlorophyll and/or carmine.
15. A process according to claim 11, wherein the suspension contains a carbohydrate in an amount of up to 70 percent by weight of the suspension.
16. A process according to claim 15, wherein the carbohydrate is sucrose.
17. A process according to claim 11, wherein the suspension further contains an antioxidant.
18. A process according to claim 11, wherein the aerophilic solid is used in an amount which is sufficient to provide a microencapsulated product having a concentration of up to 71 percent by weight of aerophilic solid.
US08/187,134 1989-11-02 1994-01-27 Process of preparing a water dispersible hydrophobic or aerophilic solid Expired - Lifetime US5460823A (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
US08/187,134 US5460823A (en) 1989-11-02 1994-01-27 Process of preparing a water dispersible hydrophobic or aerophilic solid

Applications Claiming Priority (5)

Application Number Priority Date Filing Date Title
DK546289A DK546289D0 (en) 1989-11-02 1989-11-02 carotenoid
DK5462/89 1989-11-02
PCT/DK1990/000278 WO1991006292A1 (en) 1989-11-02 1990-11-02 Process of preparing a water dispersible hydrophobic or aerophilic solid
US85564192A 1992-05-04 1992-05-04
US08/187,134 US5460823A (en) 1989-11-02 1994-01-27 Process of preparing a water dispersible hydrophobic or aerophilic solid

Related Parent Applications (1)

Application Number Title Priority Date Filing Date
US85564192A Continuation 1989-11-02 1992-05-04

Publications (1)

Publication Number Publication Date
US5460823A true US5460823A (en) 1995-10-24

Family

ID=8142640

Family Applications (1)

Application Number Title Priority Date Filing Date
US08/187,134 Expired - Lifetime US5460823A (en) 1989-11-02 1994-01-27 Process of preparing a water dispersible hydrophobic or aerophilic solid

Country Status (8)

Country Link
US (1) US5460823A (en)
EP (1) EP0498824B2 (en)
AU (1) AU6632490A (en)
CA (1) CA2072108C (en)
DE (1) DE69006362T3 (en)
DK (2) DK546289D0 (en)
ES (1) ES2062563T5 (en)
WO (1) WO1991006292A1 (en)

Cited By (30)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6007856A (en) * 1997-08-08 1999-12-28 The Procter & Gamble Company Oil-in-water dispersions of β-carotene and other carotenoids stable against oxidation prepared from water-dispersible beadlets having high concentrations of carotenoid
US6093348A (en) * 1996-05-14 2000-07-25 Roche Vitamins Inc. Process for manufacture of carotenoid compositions
DE10118979A1 (en) * 2001-04-18 2002-11-14 Markus Miller Process for the production of easily soluble agglomerates from a particularly poorly soluble bulk material
WO2003045167A1 (en) 2001-11-26 2003-06-05 Lycored Natural Products Industries Ltd. Carotenoid formulation
US6582721B1 (en) 1999-09-17 2003-06-24 Alcon, Inc. Stable carotene-xanthophyll beadlet compositions and methods of use
US20030170309A1 (en) * 2001-06-22 2003-09-11 Babcock Walter C. Pharmaceutical compositions containing polymer and drug assemblies
US20040015519A1 (en) * 2001-10-15 2004-01-22 Yukitoshi Maeda Content delivery server and content delivery system having the same
US6719839B2 (en) 1996-01-22 2004-04-13 Chr. Hansen A/S Water dispersible compositions containing natural hydrophilic water-insoluble pigments, methods of preparing same and their use
US20040156905A1 (en) * 2002-08-12 2004-08-12 Pfizer Inc. Pharmaceutical compositions of semi-ordered drugs and polymers
US20050255147A1 (en) * 2002-08-14 2005-11-17 Zoolife International Limited Composition for dietary enrichment
WO2006066389A1 (en) * 2004-12-22 2006-06-29 Colarôme Inc. Natural water-insoluble encapsulation compositions and processes for preparing same
US20070028401A1 (en) * 2003-09-15 2007-02-08 Basf Aktiengesellschaft Powdered preparations containing a mixture of 2,4,6-trianilino-p-(carbo-2'-ethylhexyl-1'-oxi)-1,3,5-triazine and diethylamino-hydroxybenzoyl-hexyl-benzoate
US20070031352A1 (en) * 2003-09-15 2007-02-08 Basf Aktiengesellschaft Powdery preparations containing diethylamino-hydroxybenzoyl-hexyl-benzoate
US20080181960A1 (en) * 2006-12-21 2008-07-31 Isp Investments, Inc. Carotenoids of enhanced bioavailability
US20090087485A1 (en) * 2006-03-31 2009-04-02 Rubicon Research Private Limited Orally Disintegrating Tablets
US20100092564A1 (en) * 2006-12-21 2010-04-15 Jae Han Park Composition of and Method for Preparing Orally Disintegrating Tablets
CN1744827B (en) * 2003-01-31 2010-05-26 帝斯曼知识产权资产管理有限公司 Novel compositions comprising carotenoids
US20110274809A1 (en) * 2010-04-16 2011-11-10 San-Ei Gen F.F.I., Inc. Method for masking curcumine flavor
CN102361561A (en) * 2009-03-30 2012-02-22 巴斯夫欧洲公司 Ready-to-use, stable suspension of partially amorphous carotenoid particles
US20120195949A1 (en) * 2009-09-28 2012-08-02 San-Ei Gen F.F.I., Inc. Turmeric pigment composition and method for preparing same
WO2014145851A1 (en) * 2013-03-15 2014-09-18 Glanbia Nutritionals (Ireland) Ltd. Product and method for improving bioavailability of therapeutic compounds
US20140364512A9 (en) * 2012-04-19 2014-12-11 Epc (Beijing) Natural Products Co., Ltd. Compositions comprising a combination of at least one colorant and at least one polysaccharide
CN105578894A (en) * 2013-09-24 2016-05-11 帝斯曼知识产权资产管理有限公司 Stable red formulations for the coloration of beverages and food
CN107404898A (en) * 2015-03-26 2017-11-28 帝斯曼知识产权资产管理有限公司 New color for soft sweets and jelly
CN107427022A (en) * 2015-03-26 2017-12-01 帝斯曼知识产权资产管理有限公司 New red color for edible coating
CN107427023A (en) * 2015-03-26 2017-12-01 帝斯曼知识产权资产管理有限公司 New color for edible coating
US10335371B2 (en) * 2015-02-17 2019-07-02 Universiteit Gent Solid pharmaceutical dosage form suitable for use as drinking water medication
US10533153B2 (en) 2013-03-13 2020-01-14 Sanofi-Aventis Deutschland Gmbh Production of squalene and/or sterol from cell suspensions of fermented yeast
WO2022112586A1 (en) * 2020-11-30 2022-06-02 Dsm Ip Assets B.V. New sugar-free formulations, their manufacture and use
WO2022112592A1 (en) * 2020-11-30 2022-06-02 Dsm Ip Assets B.V. New formulations with reduced antioxidant content, their manufacture and use

Families Citing this family (76)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5399363A (en) * 1991-01-25 1995-03-21 Eastman Kodak Company Surface modified anticancer nanoparticles
US5552160A (en) * 1991-01-25 1996-09-03 Nanosystems L.L.C. Surface modified NSAID nanoparticles
US6132790A (en) * 1991-09-06 2000-10-17 Betatene Limited Carotenoid composition
DE4140192C2 (en) * 1991-12-05 1996-02-29 Alfatec Pharma Gmbh Sol-controlled gelatin-based thermocolloid matrix for peroral sustained release forms
DE4140179C2 (en) * 1991-12-05 1995-12-21 Alfatec Pharma Gmbh Acute form for a drug containing ibuprofen
DE4140185C2 (en) * 1991-12-05 1996-02-01 Alfatec Pharma Gmbh Medicament containing a 2-arylpropionic acid derivative in nanosol form and its preparation
DE4140172C2 (en) * 1991-12-05 1995-12-21 Alfatec Pharma Gmbh Retard form for a drug containing ibuprofen
EP0616526A1 (en) * 1991-12-11 1994-09-28 The Procter & Gamble Company Cetylpyridinium chloride and domiphen bromide in organic solvent
WO1993011799A1 (en) * 1991-12-18 1993-06-24 Pfizer Inc. Soybean protein or hydrolyzates in pharmaceutical compositions to protect bioactive peptides from enzymatic inactivation
DK0644755T3 (en) * 1992-06-10 1997-09-22 Nanosystems Llc Surface Modified NSAID Nanoparticles
IL110139A0 (en) * 1993-06-28 1994-10-07 Howard Foundation Pharmaceutically-active antioxidants
US5718388A (en) * 1994-05-25 1998-02-17 Eastman Kodak Continuous method of grinding pharmaceutical substances
JPH10511270A (en) * 1995-01-31 1998-11-04 ノイロサーチ アクティーゼルスカブ Astaxanthin suspension
JPH09124470A (en) 1995-10-26 1997-05-13 Suntory Ltd Antistress composition
DE19637517A1 (en) * 1996-09-13 1998-03-19 Basf Ag Production of powdered, cold water dispersible carotenoid preparations and the use of the new carotenoid preparations
DE19651681A1 (en) * 1996-12-12 1998-06-18 Basf Ag Stable, aqueous dispersions and stable, water-dispersible dry powders of xanthophylls, their production and use
DE19653410A1 (en) 1996-12-20 1998-06-25 Basf Ag Use of carotenoid solubilisates for coloring food and pharmaceutical preparations
NL1007240C2 (en) * 1997-10-09 1999-04-27 Penta Participatiemaatschappij Method of manufacturing animal feed containing a color pigment.
DE19831865A1 (en) 1998-07-16 2000-01-20 Basf Ag Use of organic sulfur compounds as a means for bathochromic shifting of the UV / Vis absorption band of carotenoids
DE19838636A1 (en) 1998-08-26 2000-03-02 Basf Ag Carotenoid formulations containing a mixture of beta-carotene, lycopene and lutein
DE19841930A1 (en) 1998-09-14 2000-03-16 Basf Ag Stable, powdery lycopene formulations containing lycopene with a degree of crystallinity greater than 20%
DE19919751A1 (en) 1999-04-29 2000-11-09 Basf Ag Stable, aqueous dispersions and stable, water-dispersible dry powder of xanthophylls, their preparation and use
US6500473B1 (en) 1999-05-21 2002-12-31 Chr. Hansen A/S Coloring substance composition and a method of manufacturing same
DE19956848A1 (en) * 1999-11-26 2001-05-31 Basf Ag Curcumin formulations
US7105176B2 (en) 2000-11-29 2006-09-12 Basf Aktiengesellschaft Production of solid preparations of water-soluble, sparingly water-soluble or water-insoluble active compounds
DE10064387A1 (en) 2000-12-21 2002-06-27 Basf Ag Redispersible dry powder containing oxygen-containing carotenoid, useful e.g. as dye in foods, feed or pharmaceuticals, prepared in presence of partially degraded soya protein as protective colloid
US9700866B2 (en) 2000-12-22 2017-07-11 Baxter International Inc. Surfactant systems for delivery of organic compounds
US8067032B2 (en) 2000-12-22 2011-11-29 Baxter International Inc. Method for preparing submicron particles of antineoplastic agents
DE10104494A1 (en) 2001-01-31 2002-08-01 Basf Ag Process for the preparation of dry powders of one or more carotenoids
US20060003012A9 (en) 2001-09-26 2006-01-05 Sean Brynjelsen Preparation of submicron solid particle suspensions by sonication of multiphase systems
CA2461349C (en) 2001-09-26 2011-11-29 Baxter International Inc. Preparation of submicron sized nanoparticles via dispersion and solvent or liquid phase removal
DE10355400A1 (en) 2003-11-25 2005-07-07 Noack, Andreas, Dr. Multicomponent mineral preparations and method for the preparation of multi-component mineral preparations
DE102004006106A1 (en) * 2004-02-06 2005-08-25 Basf Ag Process for the preparation of dry powders of one or more carotenols
DE102004046026A1 (en) * 2004-09-21 2006-03-23 Basf Ag Process for the preparation of dry powders of one or more carotenoids
DE102005027333B4 (en) 2005-06-13 2017-04-13 Terra Nano Ltd. Nanoskalische Reaktivdesorption - a process for the preparation of colloidal drug or Vitalstoffspezies, in particular corresponding drug or nutrient concentrates and devices for carrying out the same
DE102005030952A1 (en) 2005-06-30 2007-01-18 Basf Ag Process for the preparation of an aqueous suspension and a pulverulent preparation of one or more carotenoids
CN101312655B (en) * 2005-07-20 2012-02-29 帝斯曼知识产权资产管理有限公司 Novel stabilized carotenoid compositions
WO2007014566A2 (en) * 2005-08-04 2007-02-08 Basf Aktiengesellschaft Microcapsules and their use
EP1959966B1 (en) 2005-11-28 2020-06-03 Marinus Pharmaceuticals, Inc. Ganaxolone formulations and methods for the making and use thereof
JP2010510988A (en) 2006-11-28 2010-04-08 マリナス ファーマシューティカルズ Nanoparticle formulation, method for producing the same and use thereof
EP1938807A1 (en) * 2006-12-22 2008-07-02 Basf Se Reactive powdering
EP2111125B2 (en) 2007-01-16 2016-11-16 Basf Se Liquid formulations comprising carotenoids
ES2422458T3 (en) * 2007-02-14 2013-09-11 Dsm Ip Assets Bv Procedure for the production of a powder containing carotenoids
BRPI0807583A2 (en) * 2007-02-23 2014-07-01 Basf Se USE OF WATER DISPERSABLE CAROTENOID NANOParticles, A PROCESS FOR MODULATING FLAVOR OF MATTER COMPOSITIONS, AND FLAVOR MODULATOR
NZ596594A (en) * 2007-03-15 2013-08-30 Dsm Ip Assets Bv Stabilized micronised particles
EP2011835A1 (en) 2007-07-06 2009-01-07 Chr. Hansen A/S A colouring composition comprising starch derivatives as a hydrocolloid
ES2311422B1 (en) * 2007-07-28 2009-10-13 Investigaciones Quimicas Y Farmaceuticas, S.A FORMULATION OF CAROTENOIDS AVAILABLE IN WATER.
CN101873804A (en) 2007-11-29 2010-10-27 巴斯夫欧洲公司 Pulverulent carotenoid preparation for colouring drinks
WO2009080702A1 (en) † 2007-12-21 2009-07-02 Basf Se Microcapsules comprising a fat -soluble active substance
JP5932334B2 (en) 2008-10-07 2016-06-08 ビーエーエスエフ ソシエタス・ヨーロピアＢａｓｆ Ｓｅ Stable emulsion ready for use
EP2393476B1 (en) 2009-02-04 2016-01-13 DSM IP Assets B.V. Resveratrol compositions
ES2400351T3 (en) 2009-03-05 2013-04-09 Basf Se Powder compositions of astaxanthin derivatives
EP2403360B1 (en) 2009-03-05 2016-08-10 Basf Se Formulation of astaxanthin derivatives and use thereof iii
CN101549273B (en) 2009-03-30 2011-06-15 浙江新和成股份有限公司 Method of preparing nano-dispersed high-all-trans-carotenoid microcapsules
CA2769163C (en) 2009-08-28 2017-07-04 Chr. Hansen A/S High strength carbo substances
HUE050050T2 (en) * 2013-03-04 2020-11-30 Besins Healthcare Lu Sarl Dry pharmaceutical compositions comprising active agent nanoparticles bound to carrier particles
CN104274428B (en) 2013-07-09 2016-04-13 浙江新维普添加剂有限公司 The preparation method of oil-dispersing property carotenoid formulation
WO2015052182A1 (en) * 2013-10-08 2015-04-16 Chr. Hansen Natural Colors A/S Beta-carotene formulation and use thereof in coloring edible products
PL3139904T3 (en) 2014-05-05 2021-07-05 Basf Se Formulation of fat-soluble vitamin
JP2016067300A (en) * 2014-09-30 2016-05-09 富士フイルム株式会社 Beverage composition and method of producing beverage composition
US20180027834A1 (en) 2015-02-06 2018-02-01 Basf Se Microcapsules comprising lutein or lutein ester
WO2016124783A1 (en) 2015-02-06 2016-08-11 Basf Se Microcapsules comprising lutein or lutein ester
CN107205456B (en) 2015-02-06 2021-07-16 巴斯夫欧洲公司 Microcapsules comprising lutein or lutein esters
KR20180082457A (en) 2015-10-16 2018-07-18 마리누스 파마슈티컬스 인코포레이티드 Injectable neuro-steroid agents containing nanoparticles
MX2019001669A (en) 2016-08-11 2019-09-27 Ovid Therapeutics Inc Methods and compositions for treatment of epileptic disorders.
US10391105B2 (en) 2016-09-09 2019-08-27 Marinus Pharmaceuticals Inc. Methods of treating certain depressive disorders and delirium tremens
CN109156827A (en) * 2018-09-20 2019-01-08 武汉星辰现代生物工程有限公司 A kind of preparation method of high bioavilability red colour system beta Carotene preparation
US11266662B2 (en) 2018-12-07 2022-03-08 Marinus Pharmaceuticals, Inc. Ganaxolone for use in prophylaxis and treatment of postpartum depression
CN111714466A (en) * 2019-03-18 2020-09-29 浙江医药股份有限公司新昌制药厂 Preparation method of carotenoid preparation with high bioavailability and high stability
CA3145923A1 (en) 2019-08-05 2021-02-11 David Czekai Ganaxolone for use in treatment of status epilepticus
JP2023503928A (en) 2019-12-06 2023-02-01 マリナス ファーマシューティカルズ， インコーポレイテッド Ganaxolone for use in the treatment of tuberous sclerosis
CN111718288A (en) * 2020-06-29 2020-09-29 河南中大恒源生物科技股份有限公司 Lutein ester and water-soluble lutein ester microcapsule and preparation method thereof
WO2022112585A1 (en) 2020-11-30 2022-06-02 Dsm Ip Assets B.V. New sugar-free formulations, their manufacture and use
CN116490080A (en) 2020-11-30 2023-07-25 帝斯曼知识产权资产管理有限公司 New formulation with reduced antioxidant content, its manufacture and use
WO2022129433A1 (en) 2020-12-18 2022-06-23 Dsm Ip Assets B.V. Milk replacer comprising animal-free formulations of fat-soluble vitamins
WO2022129435A1 (en) 2020-12-18 2022-06-23 Dsm Ip Assets B.V. Milk replacer comprising animal-free formulations of fat-soluble vitamins

Citations (15)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2876160A (en) * 1954-07-26 1959-03-03 Corn Prod Refining Co Starch matrix material containing imbedded material and process for preparing same
US3110598A (en) * 1959-09-08 1963-11-12 Hoffmann La Roche Process of making a carotenoid preparation
US3206316A (en) * 1960-10-17 1965-09-14 Hoffmann La Roche Water dispersible carotenoid preparations and processes thereof
CH420817A (en) * 1959-04-15 1966-09-15 Philips Nv Process for the production of a dry and scatterable preparation which is stable in the air and which contains an easily oxidizable substance
CH431252A (en) * 1960-04-07 1967-02-28 Philips Nv Process for obtaining solid, scatterable preparations containing a biologically valuable substance
US3526682A (en) * 1966-08-23 1970-09-01 Pfizer & Co C Microencapsulation of pharmaceuticals
US3529065A (en) * 1967-05-02 1970-09-15 Pfizer & Co C Process for making dry vitamin a material
US4006025A (en) * 1975-06-06 1977-02-01 Polaroid Corporation Process for dispersing sensitizing dyes
DE2820981A1 (en) * 1977-09-27 1979-04-05 Colorcon Colour pigments for coating pharmaceutical tablets
EP0034771A1 (en) * 1980-02-22 1981-09-02 Rohner AG Pratteln Highly concentrated, stably storable and heat resistent, freely flowable, aqueous dispersion of substances hardly soluble or insoluble in water, process for preparing the dispersion, process for finishing synthetic materials, paper or textiles, and the finished synthetic materials, paper and textiles
EP0074050A2 (en) * 1981-09-05 1983-03-16 BASF Aktiengesellschaft Process for preparing dry powders of oxidation-sensitive compounds
GB2122085A (en) * 1979-04-13 1984-01-11 Freund Ind Company Ltd A process for the preparation of activated pharmaceutical compositions
US4522743A (en) * 1981-05-15 1985-06-11 Basf Aktiengesellschaft Preparation of finely divided pulverulent carotinoid and retinoid compositions
US4726955A (en) * 1986-04-04 1988-02-23 Basf Aktiengesellschaft Preparation of finely divided, pulverulent carotenoid preparations
EP0333523A2 (en) * 1988-03-18 1989-09-20 The Uab Research Foundation Method of potentiating an immune response and compositions therefor

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
MC2034A1 (en) * 1988-06-23 1990-05-30 Hoffmann La Roche PREPARATIONS

Patent Citations (17)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2876160A (en) * 1954-07-26 1959-03-03 Corn Prod Refining Co Starch matrix material containing imbedded material and process for preparing same
CH420817A (en) * 1959-04-15 1966-09-15 Philips Nv Process for the production of a dry and scatterable preparation which is stable in the air and which contains an easily oxidizable substance
US3110598A (en) * 1959-09-08 1963-11-12 Hoffmann La Roche Process of making a carotenoid preparation
CH431252A (en) * 1960-04-07 1967-02-28 Philips Nv Process for obtaining solid, scatterable preparations containing a biologically valuable substance
US3206316A (en) * 1960-10-17 1965-09-14 Hoffmann La Roche Water dispersible carotenoid preparations and processes thereof
US3526682A (en) * 1966-08-23 1970-09-01 Pfizer & Co C Microencapsulation of pharmaceuticals
DE1617737A1 (en) * 1966-08-23 1972-03-09 Pfizer Process for encapsulating aqueous dispersions
US3529065A (en) * 1967-05-02 1970-09-15 Pfizer & Co C Process for making dry vitamin a material
US4006025A (en) * 1975-06-06 1977-02-01 Polaroid Corporation Process for dispersing sensitizing dyes
DE2820981A1 (en) * 1977-09-27 1979-04-05 Colorcon Colour pigments for coating pharmaceutical tablets
GB2122085A (en) * 1979-04-13 1984-01-11 Freund Ind Company Ltd A process for the preparation of activated pharmaceutical compositions
EP0034771A1 (en) * 1980-02-22 1981-09-02 Rohner AG Pratteln Highly concentrated, stably storable and heat resistent, freely flowable, aqueous dispersion of substances hardly soluble or insoluble in water, process for preparing the dispersion, process for finishing synthetic materials, paper or textiles, and the finished synthetic materials, paper and textiles
US4522743A (en) * 1981-05-15 1985-06-11 Basf Aktiengesellschaft Preparation of finely divided pulverulent carotinoid and retinoid compositions
EP0074050A2 (en) * 1981-09-05 1983-03-16 BASF Aktiengesellschaft Process for preparing dry powders of oxidation-sensitive compounds
US4519961A (en) * 1981-09-05 1985-05-28 Basf Aktiengesellschaft Production of dry powders of substances which are sensitive to oxidation
US4726955A (en) * 1986-04-04 1988-02-23 Basf Aktiengesellschaft Preparation of finely divided, pulverulent carotenoid preparations
EP0333523A2 (en) * 1988-03-18 1989-09-20 The Uab Research Foundation Method of potentiating an immune response and compositions therefor

Non-Patent Citations (12)

* Cited by examiner, † Cited by third party
Title
Bauernfeind et al., "Coloring Fat-Base Foods with--Carotene" in Food Technology, 12 (1958) pp. 527-535.
Bauernfeind et al., Coloring Fat Base Foods with Carotene in Food Technology , 12 (1958) pp. 527 535. *
Dialog Information Services, File 350: World Patent Index 1963 1980, WPI Acc. No. 78 4130A/26 & RD,A, 1700 64, 10 Jun. 1978 (Abstract). *
Dialog Information Services, File 350: World Patent Index 1963-1980, WPI Acc. No. 78-4130A/26 & RD,A, 1700 64, 10 Jun. 1978 (Abstract).
Lee, Chen Hsiung, Synthesis and Characterization . . . , 1976, dissertation, pp. 9 and 113. *
Lee, Chen-Hsiung, "Synthesis and Characterization . . . ", 1976, dissertation, pp. 9 and 113.
Merck Index, 10th edition, 1983, pp. 258 259. *
Merck Index, 10th edition, 1983, pp. 258-259.
Verlag Paul Parey, "Toxikologisch-hygienische . . . ", 1987, pp. 130 and 136-139.
Verlag Paul Parey, Toxikologisch hygienische . . . , 1987, pp. 130 and 136 139. *
Walford (ed.), Development in Food Colours 1, 1980, pp. 68 69. *
Walford (ed.), Development in Food Colours 1, 1980, pp. 68-69.

Cited By (53)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20060118000A1 (en) * 1996-01-22 2006-06-08 Chr-Hansen A/S Water dispersible compositions containing natural hydrophilic water-insoluble pigments, methods of preparing same and their use
US7229490B2 (en) 1996-01-22 2007-06-12 Chr. Hansen A/S Water dispersible compositions containing natural hydrophilic water-insoluble pigments, methods of preparing same and their use
US6719839B2 (en) 1996-01-22 2004-04-13 Chr. Hansen A/S Water dispersible compositions containing natural hydrophilic water-insoluble pigments, methods of preparing same and their use
US6093348A (en) * 1996-05-14 2000-07-25 Roche Vitamins Inc. Process for manufacture of carotenoid compositions
US6007856A (en) * 1997-08-08 1999-12-28 The Procter & Gamble Company Oil-in-water dispersions of β-carotene and other carotenoids stable against oxidation prepared from water-dispersible beadlets having high concentrations of carotenoid
US6582721B1 (en) 1999-09-17 2003-06-24 Alcon, Inc. Stable carotene-xanthophyll beadlet compositions and methods of use
US6716447B1 (en) 1999-09-17 2004-04-06 Alcon, Inc. Stable carotene xanthophyll beadlet compositions and methods of use
DE10118979A1 (en) * 2001-04-18 2002-11-14 Markus Miller Process for the production of easily soluble agglomerates from a particularly poorly soluble bulk material
US20030170309A1 (en) * 2001-06-22 2003-09-11 Babcock Walter C. Pharmaceutical compositions containing polymer and drug assemblies
US20040015519A1 (en) * 2001-10-15 2004-01-22 Yukitoshi Maeda Content delivery server and content delivery system having the same
US20050175561A1 (en) * 2001-11-26 2005-08-11 Lycored Natural Products Industries Ltd. Carotenoid formulation
CN100456961C (en) * 2001-11-26 2009-02-04 利库德天然产品工业有限公司 Carotenoid formulation
US10206965B2 (en) 2001-11-26 2019-02-19 Lycored Natural Products Industries Ltd. Carotenoid formulation
WO2003045167A1 (en) 2001-11-26 2003-06-05 Lycored Natural Products Industries Ltd. Carotenoid formulation
AU2009200943B2 (en) * 2001-11-26 2011-05-26 Lycored Natural Products Industries Ltd Carotenoid formulation
US20080287551A1 (en) * 2001-11-26 2008-11-20 Lycored Natural Products Industries Ltd. Carotenoid formulation
AU2002356404B2 (en) * 2001-11-26 2008-12-11 Lycored Natural Products Industries Ltd. Carotenoid formulation
US20040156905A1 (en) * 2002-08-12 2004-08-12 Pfizer Inc. Pharmaceutical compositions of semi-ordered drugs and polymers
US8491933B2 (en) 2002-08-12 2013-07-23 Bend Research, Inc. Pharmaceutical compositions of semi-ordered drugs and polymers
US8257739B2 (en) 2002-08-12 2012-09-04 Bend Research, Inc. Pharmaceutical compositions of semi-ordered drugs and polymers
US20050255147A1 (en) * 2002-08-14 2005-11-17 Zoolife International Limited Composition for dietary enrichment
CN1744827B (en) * 2003-01-31 2010-05-26 帝斯曼知识产权资产管理有限公司 Novel compositions comprising carotenoids
US20070028401A1 (en) * 2003-09-15 2007-02-08 Basf Aktiengesellschaft Powdered preparations containing a mixture of 2,4,6-trianilino-p-(carbo-2'-ethylhexyl-1'-oxi)-1,3,5-triazine and diethylamino-hydroxybenzoyl-hexyl-benzoate
US20070031352A1 (en) * 2003-09-15 2007-02-08 Basf Aktiengesellschaft Powdery preparations containing diethylamino-hydroxybenzoyl-hexyl-benzoate
US10981136B2 (en) 2004-12-22 2021-04-20 Capol Inc. Natural water-insoluble encapsulation compositions and processes for preparing same
EP1828331A1 (en) * 2004-12-22 2007-09-05 Colarôme Inc. Natural water-insoluble encapsulation compositions and processes for preparing same
WO2006066389A1 (en) * 2004-12-22 2006-06-29 Colarôme Inc. Natural water-insoluble encapsulation compositions and processes for preparing same
US20080160084A1 (en) * 2004-12-22 2008-07-03 Colarome, Inc. Natural Water-Insoluble Encapsulation Compositions and Processes for Preparing Same
US9687807B2 (en) 2004-12-22 2017-06-27 Colarome, Inc. Natural water-insoluble encapsulation compositions and processes for preparing same
EP1828331A4 (en) * 2004-12-22 2012-10-03 Colarome Inc Natural water-insoluble encapsulation compositions and processes for preparing same
US20090087485A1 (en) * 2006-03-31 2009-04-02 Rubicon Research Private Limited Orally Disintegrating Tablets
US8545890B2 (en) 2006-03-31 2013-10-01 Rubicon Research Private Limited Orally disintegrating tablets
US8613946B2 (en) * 2006-12-21 2013-12-24 Isp Investment Inc. Carotenoids of enhanced bioavailability
US20080181960A1 (en) * 2006-12-21 2008-07-31 Isp Investments, Inc. Carotenoids of enhanced bioavailability
US20100092564A1 (en) * 2006-12-21 2010-04-15 Jae Han Park Composition of and Method for Preparing Orally Disintegrating Tablets
CN102361561A (en) * 2009-03-30 2012-02-22 巴斯夫欧洲公司 Ready-to-use, stable suspension of partially amorphous carotenoid particles
US20120195949A1 (en) * 2009-09-28 2012-08-02 San-Ei Gen F.F.I., Inc. Turmeric pigment composition and method for preparing same
US10023745B2 (en) * 2009-09-28 2018-07-17 San-Ei Gen F.F.I., Inc. Turmeric pigment composition and method for preparing same
US20110274809A1 (en) * 2010-04-16 2011-11-10 San-Ei Gen F.F.I., Inc. Method for masking curcumine flavor
US10349670B2 (en) * 2010-04-16 2019-07-16 San-Ei Gen F.F.I., Inc. Method for masking curcumin flavor
US20140364512A9 (en) * 2012-04-19 2014-12-11 Epc (Beijing) Natural Products Co., Ltd. Compositions comprising a combination of at least one colorant and at least one polysaccharide
US10533153B2 (en) 2013-03-13 2020-01-14 Sanofi-Aventis Deutschland Gmbh Production of squalene and/or sterol from cell suspensions of fermented yeast
CN105491988A (en) * 2013-03-15 2016-04-13 格兰比亚营养物(爱尔兰)有限公司 Product and method for improving bioavailability of therapeutic compounds
EP2968070A4 (en) * 2013-03-15 2016-10-26 Glanbia Nutritionals Ireland Ltd Product and method for improving bioavailability of therapeutic compounds
WO2014145851A1 (en) * 2013-03-15 2014-09-18 Glanbia Nutritionals (Ireland) Ltd. Product and method for improving bioavailability of therapeutic compounds
US20160219909A1 (en) * 2013-09-24 2016-08-04 Dsm Ip Assets B.V. Stable red formulations for the coloration of beverages and food
CN105578894A (en) * 2013-09-24 2016-05-11 帝斯曼知识产权资产管理有限公司 Stable red formulations for the coloration of beverages and food
US10335371B2 (en) * 2015-02-17 2019-07-02 Universiteit Gent Solid pharmaceutical dosage form suitable for use as drinking water medication
CN107427022A (en) * 2015-03-26 2017-12-01 帝斯曼知识产权资产管理有限公司 New red color for edible coating
CN107427023A (en) * 2015-03-26 2017-12-01 帝斯曼知识产权资产管理有限公司 New color for edible coating
CN107404898A (en) * 2015-03-26 2017-11-28 帝斯曼知识产权资产管理有限公司 New color for soft sweets and jelly
WO2022112586A1 (en) * 2020-11-30 2022-06-02 Dsm Ip Assets B.V. New sugar-free formulations, their manufacture and use
WO2022112592A1 (en) * 2020-11-30 2022-06-02 Dsm Ip Assets B.V. New formulations with reduced antioxidant content, their manufacture and use

Also Published As

Publication number Publication date
CA2072108C (en) 2001-01-23
ES2062563T3 (en) 1994-12-16
DK0498824T4 (en) 1999-08-09
WO1991006292A1 (en) 1991-05-16
EP0498824B2 (en) 1998-11-25
DE69006362D1 (en) 1994-03-10
EP0498824A1 (en) 1992-08-19
DE69006362T3 (en) 1999-06-17
AU6632490A (en) 1991-05-31
CA2072108A1 (en) 1991-05-03
DE69006362T2 (en) 1994-09-01
DK0498824T3 (en) 1994-06-06
EP0498824B1 (en) 1994-01-26
DK546289D0 (en) 1989-11-02
ES2062563T5 (en) 1999-03-16

Similar Documents

Publication Publication Date Title
US5460823A (en) Process of preparing a water dispersible hydrophobic or aerophilic solid
JP3961070B2 (en) Method for producing carotenoid composition
EP0937412B1 (en) Preparation of a finely divided pulverous carotenoid preparation
JP4608034B2 (en) Liquid carotenoid preparations mixable with oil
JP4124821B2 (en) Stable aqueous dispersions of xanthophylls and stable water-dispersible dry powders, their production and use
AU743477B2 (en) The production of carotenoid preparations in the form of coldwater-dispersible powders, and the use of the novel carotenoid preparations
EP1794238B1 (en) Method for producing dry powders of at least one carotenoid
JP2620277B2 (en) Powdery water-dispersible carotenoid preparation and process for producing the same
JP3694268B2 (en) Method for producing a dry powder containing one or more carotenoids
JP2006514829A (en) Powdered phytosterol formulation
JP2011505125A (en) Carotenoid powder composition for beverage coloring
MXPA99001754A (en) Continuous procedure for the preparation of a composition in the form of powder of a carotenoid and preparation in form of dust prepared through such procedimie
JPH0335347B2 (en)
JP2008544973A (en) Aqueous suspension of poorly water-soluble or water-insoluble active substance and dry powder prepared therefrom
JP3595300B2 (en) Preparation of dry powder of one or more oxidized carotenoids
WO2008087139A1 (en) Unctuous compositions
JP2002187837A (en) Method for producing water-soluble preparation containing finely pulverized carotenoid
JP2002523350A (en) Fish gelatinous composition for use as an ingredient in tablets

Legal Events

Date Code Title Description
STCF Information on status: patent grant

Free format text: PATENTED CASE

CC Certificate of correction
FEPP Fee payment procedure

Free format text: PAT HLDR NO LONGER CLAIMS SMALL ENT STAT AS INDIV INVENTOR (ORIGINAL EVENT CODE: LSM1); ENTITY STATUS OF PATENT OWNER: LARGE ENTITY

FPAY Fee payment

Year of fee payment: 4

FPAY Fee payment

Year of fee payment: 8

FEPP Fee payment procedure

Free format text: PAYER NUMBER DE-ASSIGNED (ORIGINAL EVENT CODE: RMPN); ENTITY STATUS OF PATENT OWNER: LARGE ENTITY

Free format text: PAYOR NUMBER ASSIGNED (ORIGINAL EVENT CODE: ASPN); ENTITY STATUS OF PATENT OWNER: LARGE ENTITY

FPAY Fee payment

Year of fee payment: 12